Neurodevelopmental outcome following Nitric Oxide Therapy for Persistent Pulmonary Hypertension in Term Newborn Infants
Date First Published:
August 8, 2003
Last Updated:
November 12, 2003
Report by:
Jon Dorling, Clinical Lecturer (Neonatal Intensive Care Unit, Leicester Royal Infirmary)
Search checked by:
tbc, Neonatal Intensive Care Unit, Leicester Royal Infirmary
Three-Part Question:
In [a term infant with severe Persistent Pulmonary Hypertension of the Newborn] does [inhaled nitric oxide therapy] [improve the long term neurodevelopmental prognosis]?
Clinical Scenario:
A 41 week gestation male infant, birth weight 4320g, is born by an emergency caesarean section at a District General Hospital for fetal distress and a poor fetal scalp blood gas. The infant is in poor condition at birth and requires intubation and ventilation. As the Tertiary Neonatal transport fellow you are called to transfer the infant to the Tertiary unit as he is hypoxic despite 100% oxygen and a peak pressure of 32. You calculate his oxygenation index to be 32. Your Consultant talks you through the use of the portable Nitric oxide equipment before you leave. You wonder what the long term neurodevelopment effect of Nitric oxide is in Term babies.
Search Strategy:
Cochrane Library and Pubmed
Search Details:
Cochrane: Searching for nitric oxide and term infant – 1 systematic review (Finer)
PubMed: searching for Nitric oxide"[MeSH], Limits: Newborn: birth-1 month AND randomised controlled trial
PubMed: searching for Nitric oxide"[MeSH], Limits: Newborn: birth-1 month AND randomised controlled trial
Outcome:
1 Cochrane systematic review
Pubmed - 6 relevant papers
Pubmed - 6 relevant papers
Relevant Paper(s):
| Study Title | Patient Group | Study type (level of evidence) | Outcomes | Key results | Study Weaknesses |
|---|---|---|---|---|---|
| Nitric oxide for respiratory failure in infants born at or near term. Finer NN, Barrington KJ. 03-Jun-01 USA | Term and near-term (>34 weeks gestation), newborn infants (< 1 month of age) with persistent pulmonary hypertension | Systematic review (level 1a) | Reports data only from Ninos paper and comments on Ellington paper. Please see individual analysis of those papers. | ||
| Cost-effectiveness of inhaled nitric oxide in near-term and term infants with respiratory failure: eighteen- to 24-month follow-up for Canadian patients. Jacobs P, Finer NN, Fassbender K, Hall E, Robertson CM. Ocotober 2002 Canada | Term and near-term neonates with severe respiratory failure (at least 2 oxygenation indexes >/=25 at least 15 mins apart) | RCT (level 1b evidence) | Data reported from Canadian infants also included in NINOS paper. | ||
| Neurodevelopmental and medical outcomes of persistent pulmonary hypertension in term newborns treated with nitric oxide. Lipkin PH, Davidson D, Spivak L, Straube R, Rhines J, Chang CT. Mar-02 USA | Term infants with PPHN | Randomized Controlled Trial (level 1b) | Normal Motor outcome | C 82%, T 76% (n=35 & 87) | No confidence intervals or actual p values given. Power calculation not described, but recruitment only half of aim. Follow-up publication of the Davidson paper |
| Normal Cognitive outcome | C 71%, T 69% (n=35 & 87) | ||||
| Major Neurological abnormality | C 11%, T 14% (n=35 & 87) | ||||
| Child health status, neurodevelopmental outcome, and parental satisfaction in a randomized, controlled trial of nitric oxide for persistent pulmonary hypertension of the newborn. Ellington M Jr, O'Reilly D, Allred EN, McCormick MC, Wessel DL, Kourembanas S. Jun-01 USA | Term or near term infants (>34 weeks gestational age) with PPHN. | RCT (level 1b) | Disability | p=0.26 (T 9% v C 20%) | Poor follow up rate (72% overall, 81% Treatment, 63% controls) and small numbers (25 controls followed up) No power calculation |
| Visual Disability | p=0.3 (T 12%, C 3%) | ||||
| Hearing or Speech Disability | p=0.17 (T 11%, C 28%) | ||||
| Developmental Quotient (Median) | p=0.42 (T 102 v C 99) | ||||
| Developmental Quotient <70 | p= 0.03 (T 0%, C 16%) | ||||
| Inhaled nitric oxide in term and near-term infants: neurodevelopmental follow-up of the neonatal inhaled nitric oxide study group (NINOS). No authors listed (NINOS). May-00 | Hypoxic infants >/=34 weeks' gestation and <14 days of age | RCT (level 1b) | Cerebral Palsy | C 9 (10.3%) v T 10 (11.8%) | Secondary analysis of trial of INO for mortality. Inadequate numbers to show significant difference and no power calculation. Showed difference in seizures after discharge but multiple analyses and no use of the Bonferroni method to correct for this (may be a chance finding). |
| Seizures since discharge | C 13 (14.9%) v T 4 (4.7%), p=0.046 | ||||
| Blind in one or both eyes | C 2 v T 2 | ||||
| Hearing normal | C 59 (72%) v T 51 (68%) | ||||
| Bayley scales MDI <70 | C 14 (19.2%) v T 21 (27.3%) | ||||
| Mean Bayley Scale MDI | C 87.0 (+/- 18.7) v T 85 (+/- 21.7) | ||||
| Mean Bayley Scale PDI | C 93.6 (+/- 17.5) v T 85.7 (+/- 21.2) | ||||
| Inhaled nitric oxide for the early treatment of persistent pulmonary hypertension of the term newborn: a randomized, double-masked, placebo-controlled, dose-response, multicenter study. Davidson D, Barefield ES, Kattwinkel J, Dudell G, Damask M, Straube R, Rhines J, Chang CT. Mar-98 USA | Term infants (>37 weeks gestation, >2.5kg, <72 hours old) needing ventilation with 100% oxygen | RCT (level 1b) | Abnormal cranial ultrasound | control 10% , Treatment 5% | Failed to recruit anticipated number (studied only 155 of 320 aim) Neurologic sequelae studied until 28 days only, 1 year follow mentioned but not reported. Confidence Intervals or relative risks not given for outcomes |
| Abnormal neonatal neurology | Control 26%, Treatment 24% |
Author Commentary:
Studies to date have not so far shown statistical evidence of abnormal development or poor neurological sequelae. At present insufficient subjects have been assessed for neurodevelopmetal outcomes. Further data is needed before a harmful effect of nitric oxide on neurodevelopment can be excluded.
Bottom Line:
Insufficient evidence exists currently: a beneficial or harmful effect of nitric oxide on neurodevelopment cannot be excluded.
References:
- Finer NN, Barrington KJ.. Nitric oxide for respiratory failure in infants born at or near term.
- Jacobs P, Finer NN, Fassbender K, Hall E, Robertson CM.. Cost-effectiveness of inhaled nitric oxide in near-term and term infants with respiratory failure: eighteen- to 24-month follow-up for Canadian patients.
- Lipkin PH, Davidson D, Spivak L, Straube R, Rhines J, Chang CT.. Neurodevelopmental and medical outcomes of persistent pulmonary hypertension in term newborns treated with nitric oxide.
- Ellington M Jr, O'Reilly D, Allred EN, McCormick MC, Wessel DL, Kourembanas S.. Child health status, neurodevelopmental outcome, and parental satisfaction in a randomized, controlled trial of nitric oxide for persistent pulmonary hypertension of the newborn.
- No authors listed (NINOS).. Inhaled nitric oxide in term and near-term infants: neurodevelopmental follow-up of the neonatal inhaled nitric oxide study group (NINOS).
- Davidson D, Barefield ES, Kattwinkel J, Dudell G, Damask M, Straube R, Rhines J, Chang CT.. Inhaled nitric oxide for the early treatment of persistent pulmonary hypertension of the term newborn: a randomized, double-masked, placebo-controlled, dose-response, multicenter study.